Skin cancer or melanoma is the most commonly found type of cancer. Even though melanoma represents only 4% of the total number of cases, it is responsible for about 79% of cancer deaths. According to statistics provided by the American Cancer Society, in contrast to many other types of cancers, the number of new cases of melanoma in the United States is still on the rise, currently at the rate of about 3% a year.
In the past three decades, virtually no therapeutic advances have been made that would increase the survival rate of patients with late stage of melanoma. The current survival rate is about 3-9%,
As with all cancers, it is imperative to catch melanoma early. About 70% of melanomas are “superficial spreading”, meaning that they undergo a superficial, radial growth phase before they grow vertically and invade underlying tissue, a much more serious condition. Unfortunately, about 20% of cutaneous melanomas immediately start out with a vertical growth phase, which explains why these tumors are so dangerous. The 5-year survival rate for Stage 1 melanoma is very good, about 80-95%. However, this drops off rapidly when cancer is allowed to progress and invade, first locally and then more distantly. Survival rate for Stage 2 disease is only 40-80%, Stage III 10-70% and Stage 4 is almost invariable lethal within 5 years (<5-10% survives beyond 5 years) due to untreatable distant metastasis to especially lung and brain.
Melanoma originates from malignant transformation of melanocytes, the pigment producing skin cells, via atypical and dysplastic premalignant intermediate stages to locally invasive and finally metastatic melanoma. A large number of genes have been implicated to play a role in these processes such as H-Ras, bFGF, c-Kit/SCF and EGFR. Recently, attention has focused on p14ARF and the CDK inhibitor p16INK4a which was identified as a susceptibility gene in familial melanoma. Many other factors are likely involved.
Melanoma is one of most difficult malignancies to classify histologically. This contributes greatly to its problematic diagnosis, prognosis and treatment.
For the pathologist, the best prognostic indicator available currently is the depth or vertical growth of the lesion, i.e. tumor thickness, which is clearly associated with a poor prognosis. However, the tumor itself can present a real problem because it is typically heterogenous even within the same lesion. The cells can have many different sizes, shapes and colors, making it often difficult to pinpoint the diagnosis. The histological determination of melanoma is even more difficult with atypical melanocytes. Such melanocytes can either be completely benign, or they can be premalignant with a high probability of progressing into melanoma, which greatly hampers the accuracy of diagnostic and treatment decisions offered to the patient.
To assist the dermatopathologist in his diagnosis, currently available tools include, for example, morphometry, DNA ploidy, chromosome and nucleolar organizing analyses.
However, immunohistochemistry, which uses specific antibodies generated against melanoma-associated proteins to find whether specific markers are expressed in suspect tissue remains the preferred technique because it is relatively simple, it can be automated, it is quick, reproducible and commonly used in modern hospitals.
A large variety of these molecular “melanoma biomarkers” have been identified, and while most have been found to be of no or only limited value in the clinic, there are some, e.g. MCAM, S100, TRP1 and gp100/HMB45 that are used on a routine basis in the attempts to establish a melanoma diagnosis. Another marker is MiTF (micro-ophthalmia tissue factor). To increase the value and reliability of these markers, typically a panel of different markers is used. This consumes more time and finances than if a single antibody could be used. Moreover, even the results derived from panels of markers is often not of sufficient enough quality to make a reliable diagnosis. Specifically, metastasizing tumors can present a problem because they are even more heterogenous than primary tumors, making them difficult to analyze. Additionally, there is also no specific marker for atypical and potentially premalignant melanocytes that can distinguish them from benign melanocytes. These are significant problems facing dermatology pathologists.
The typical treatment option for melanoma patients is surgery, which is highly effective when the tumor is still local and in its radial growth phase. If the tumor is more invasive, surgery can be combined with radiation and/or chemotherapy. Since these conventional modalities cannot cure patients of lethal metastasized tumors, efficacy of alternative treatments such as immunotherapy are being investigated in clinical trials. However, currently there is essentially still no cure for advanced stage disease despite decades of research.
Metastatic melanoma, the usual cause of death, is notoriously resistant to conventional therapy, and only improved understanding of the genetics of this disease can be expected to lead to new therapeutic breakthroughs. Although much progress has been made in this regard (1), few, if any, significant new pharmacologic targets or therapies have come to the clinic. Immuno and biochemotherapy remain the most promising strategies (2,3), although even here the scarcity of tumor-specific cell surface proteins has largely prevented development of antibody-based therapies (3).
Thus, more targets, ideally those on the cell surface, are urgently needed for both diagnostic and various types of intervention therapies.